Insulin resistance is concomitant with type II diabetes, obesity, hypertension, and other features of the metabolic syndrome (DeFronzo (2004) Med. Clin. North. Am., 88:787-835). It is the major risk factor for cardiovascular diseases and one of the leading causes of mortality and morbidity. Proper management of insulin resistance has been shown to play a pivotal role in the reduced risk for cardiovascular diseases. However, compounds which improve the sensitivity of insulin are somewhat limited. Compounds such as pioglitazone augment the action of insulin by increasing insulin sensitivity and may be of benefit for the long-term treatment for type II diabetes. The mineral chromium is thought to play a key role in normal carbohydrate metabolism by potentiating the action of insulin, leading to increased insulin sensitivity in type II diabetes and obesity (Anderson (2000) Diabetes Metab., 26:22-27). Dietary deficiency of chromium has been shown to increase the risk of developing diabetes (Jeejeebhoy et al. (1977) Am. J. Clin. Nutr., 30:531-538). Clinical trials have demonstrated that supplementation with chromium chloride or chromium picolinate can lower blood glucose levels in diabetic patients (Morris et al. (2000) Diabet. Med., 17:684-685).
Better bioavailability of low-molecular-weight organic chromium complexes as compared to chromium salts (2-5% versus 0.5-2%) has led to the development of low-molecular-weight organic complexes of chromium as therapeutic agents to counter the diminished insulin effect under type II diabetes (Vincent (2004) Proc. Nutr. Soc., 63:41-47). Emerging evidence has shown that the biologically active form of chromium is a chromium-oligopeptide complex, which further justifies the use of organic-chromium-complexes as biomimetic chromium supplements (Yamamoto et al. (1987) Eur. J. Biochem., 165:627-631). U.S. Pat. No. 6,149,948 also demonstrates the ability of chromium containing complexes to decrease plasma cholesterol and triglycerides (see also Clodfelder et al. (2005) J. Biol. Inorg. Chem. 10:119-130; Cefalu et al. (2002) J. Nutr. 132: 1107-1114). The chromium complex of picolinic acid, one of the most popularly used dietary supplements has been shown to modulate intracellular pathways of glucose metabolism and improve comorbidities associated with insulin resistance in several animal and human studies (Anderson et al. (1997) Diabetes, 46:1786-1791; Lee and Reasner (1994) Diabetes Care, 17:1449-1452). However, recent reports have indicated that the picolinate ligand may shift the redox potential of chromium in the complex such that it can be reduced by biological reductants to generate hydroxyl radicals causing deleterious DNA mutations (Stearns et al. (1995) FASEB J., 9:1643-1648; Bagchi et al. (2002) Toxicology, 180:5-22). This pro-oxidant nature of chromium picolinate may greatly limited its therapeutic applications.